PROJECT SUMMARY Project 1 The nature of gene-by-diet interactions in obesity and other metabolic syndrome (MetSyn) traits is not well understood. Such interactions are likely to be key in understanding the worldwide ?epidemic of obesity?, particularly given the recent data implicating gut microbiota in cardio-metabolic traits. We propose a three- pronged approach to the problem. First, we will dissect gene-by-diet interactions affecting MetSyn traits (obesity, insulin resistance, fatty liver, plasma lipids) in a mouse population, the Hybrid Mouse Diversity Panel, that enables fine genetic mapping using association. Second, we will identify the underlying biochemical pathways using a systems genetics approach that allows us to follow the flow of information from DNA to transcriptome to proteome to metabolome to gut microbiome to MetSyn traits. Third, we will extend these findings to a human population, the METabolic Syndrome In Man (METSIM) study which consists of more than 10,000 men from Kuopio, Finland, that have been exquisitely characterized for MetSyn clinical traits, DNA variation and adipose tissue molecular phenotypes. The results will define mechanisms and genetic variations that underlie the striking divergent responses of individuals to unhealthy ?Western?-style diets rich in fat and sugar.